Although bipolar disorder (BP) is a common and debilitating psychiatric disorder, it is largely treatable as 50% of BP patients respond to lithium and another 20-30% respond to other medications. However, it can take multiple rounds of medication trials for mood stabilization to occur, during which time the illness progresses. Thus, a reliable predictor of lithium response is needed to reduce the time it takes achieve mood stabilization in BP patients. The long-term goal of this K01 application is to identify neuroimaging and genetic biomarkers that can reliably predict response to treatment with lithium in BP patients. The candidate is a junior faculty member with experience in genetic epidemiology and psychiatric genetics who now aims to develop expertise in neuroimaging and computational neuroanatomy. The candidate aims to conduct imaging genetics studies to help uncover the neurobiological underpinnings of BP and treatment response. We propose to utilize innovative approaches to investigate structural changes in amygdala correlated with response to lithium treatment in BP patients and to identify genetic markers associated with these structural changes. Specifically, we aim to: 1) obtain structural MR images from our state-of-the-art 7 Tesla instrument; 2) test for structural changes in amygdala related to response to treatment with lithium assessed prospectively in 60 BP patients after lithium monotherapy; and 3) identify genetic variants associated with the observed neuroimaging biomarker. We expect to detect larger amygdala size associated with a positive response to lithium, and to identify associated lithium response candidate genes. Identifying biomarkers that can predict response to lithium in BP will inform treatment decisions and contribute towards better outcomes for those suffering from this disorder. Gaining a better understanding of lithium response will also help shed light on the mechanism of action of lithium and the underlying etiology of BP. This training and research proposal will also enable the candidate to develop into an independent investigator in imaging genetics. Dr. James Potash, Director of Mood Disorders Research at Johns Hopkins, will serve as the primary mentor. Co-mentors include Dr. Peter van Zijl, Director of the F.M. Kirby Research Center for Functional Brain Imaging, a physicist and an expert in MRI technologies, and Dr. Michael Miller, Director of the Center for Imaging Science, a biomedical engineer and a leading authority on computational neuroanatomy. PUBLIC HEALTH RELEVANCE: While bipolar disorder affects 1-3% of the U.S. population and is one of the top ten worldwide causes of disability, the illness is largely treatable as many patients respond to lithium treatment, often the first-line agent, and others respond to additional medications. Currently the process of finding the right medication for a given patient involves trial and error, which can take months to years, and in this period patients and their families often experience instability and misery, as well as life-threatening situations in many cases. The goal of this project is to identify neuroimaging and genetic biomarkers that can reliably predict response to treatment with lithium in BP patients, thus improving clinical outcomes, and also shedding light on the mechanism of action of the drug.